Medically reviewed by Kornelia Polyak, MD, PhD
In the jostling, jockeying mob of cell populations within a malignant tumor, the most inconspicuous groups can be the most dangerous. In a new study, Dana-Farber scientists show that in some breast cancers, two small factions of cells cooperate to drive metastasis but don’t directly interact with each other. Instead, they cause nearby noncancerous cells to become their accomplices.
The findings, published in Nature Cell Biology, have implications both in principle and in practice. They demonstrate that minor subsets of tumor cells can have a major — even a decisive — role in metastasis, and that nontumor cells can be active participants in tumor spread. They also suggest that drugs targeting the two subsets identified by Dana-Farber investigators could thwart the metastatic process in some cancers.
The research is part of a larger effort to understand how the motley nature of tumors affects their behavior. Many tumors are not uniform throughout but are mixtures of groups of cells, called subclones, with distinct sets of genetic abnormalities. Scientists are interested in what this inner diversity implies for tumors’ ability to grow, spread, and respond to or resist therapy. Ultimately, they hope this knowledge will make for better treatments, by targeting the cells — cancerous and noncancerous — most responsible for metastasis.
“In earlier research, we created a model of human breast cancer that contains multiple subclones,” says Dana-Farber’s Kornelia Polyak, MD, PhD, who led the study with Michalina Janiszewska, PhD, and Doris Tabassum, PhD, of her lab. “We showed that tumors with 18 subclones grew the fastest and were highly metastatic, and that tumors made up of just two subclones — one expressing the protein IL11 and one expressing the FIGF protein — had these same characteristics. When we eliminated IL11-expressing cells from the 18-subclone model, tumor growth decreased, suggesting that IL11 and FIGF cooperate to drive growth and metastasis.”
The goal of the new study was to uncover how the IL11- and FIGF-expressing subclones — which together constitute less than 5% of all the cells in the breast tumor model used by researchers — collaborate to make tumors so aggressive, and why tumors and their metastatic growths are often composed of multiple subclones, some of which spur tumor growth and some of which don’t. The answer to both questions, it turns out, is that the “collaboration” between the IL11 and FIGF subclones is more inadvertent than conspiratorial – more a matter of enlisting outside assistance than of working together.
To explore the nature of this cooperation, researchers constructed tumors in which 10% of the cells expressed IL11 (a group known as the IL11+ subclone), 10% expressed FIGF (the FIGF+subclone), and the remaining 80% were two “neutral” subclones that do not, by themselves, spark tumor growth and metastasis. They profiled the tumors’ genomic activity and found that certain genes responsible for the tumor’s relationship with neighboring immune system cells were especially active. This suggested that the IL11+ and FIGF+ subclones promote metastasis by meddling with the tumor’s immune “microenvironment.”
“We also analyzed the relative size of IL11+ and FIGF+ subclones within the polyclonal tumors [tumors made up of multiple subclones] and found that they remained minor components,” Polyak said. “This indicates that their ability to drive tumor growth and metastasis doesn’t require an expansion of their presence within the tumor. From this we conclude that the tumor cells do not promote metastasis autonomously – that the microenvironment plays a role as well.”
The researchers then focused on the specific immune system changes brought about by breast tumors capable of metastasizing. In mice carrying such tumors, they looked for changes in white blood cells — agents of the immune system — in the initial tumor, the lungs, and the bone marrow. They found that animals whose tumors contained the IL11+ subclone had a relative increase in the number of neutrophils, white blood cells that defend against infections. When researchers depleted the animals’ neutrophil counts, metastasis was prevented.
Neutrophils’ apparent role in easing tumor growth might seem puzzling. Neutrophils are, after all, part of the immune system and by rights should be attacking tumors, not abetting their spread. Polyak and her associates found, however, that the neutrophils in and around metastasis-ready breast tumors were not activated. That is, instead of leading a broader immune system attack on the tumors, as switched-on neutrophils do, these neutrophils were essentially lending metastasis a hand. The investigators then traced how this happens: the IL11 protein acts on certain cells in the stroma – the supportive tissue of the breast and other organs – to generate tumor-friendly, metastasis-favoring neutrophils.
“Our results show how FIGF and IL11 cooperate to drive metastasis,” Polyak relates. “FIGF, which plays a role in forming blood and lymph vessels and making them leaky, creates new ‘escape routes’ for cells from a primary tumor. But that, on its own, isn’t enough to drive metastasis. IL11 acts on white blood cells in a way that makes the microenvironment of distant organs more receptive to metastatic cancer cells. Together, the IL11+and FIGF+ subclones within a tumor can be a powerful force for metastasis, even when they represent a small fraction of all the cells within the tumor and even though they don’t physically interact with each other.”